Aging Causes Collateral Rarefaction and Increased Severity of Ischemic Injury in Multiple Tissues

Abstract

Objective Aging is a major risk factor for increased ischemic tissue injury. Whether collateral rarefaction and impaired remodeling contribute to this is unknown. We quantified the number and diameter of native collaterals, and their remodeling in 3-, 16-, 24-, and 31-months-old mice. Methods and Results Aging caused an “age-dose-dependent” greater drop in perfusion immediately after femoral artery ligation, followed by a diminished recovery of flow and increase in tissue injury. These effects were associated with a decline in collateral number, diameter and remodeling. Angiogenesis was also impaired. Mechanistically, these changes were not accompanied by reduced recruitment of T-cells or macrophages to remodeling collaterals. However, eNOS signaling was dysfunctional, as indicated by increased protein nitrosylation and less phosphorylated eNOS and VASP in collateral wall cells. The cerebral circulation exhibited a similar age-dose-dependent loss of collateral number and diameter and increased tortuosity, resulting in an increase in collateral resistance and infarct volume (e.g., 6- and 3-fold, respectively, in 24-months-old mice) after artery occlusion. This was not associated with rarefaction of similarly-sized arterioles. Collateral remodeling was also reduced. Conclusions Our findings demonstrate that aging causes rarefaction and insufficiency of the collateral circulation in multiple tissues, resulting in more severe ischemic tissue injury.

Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40−/−mice

“…In the severe surgery the femoral artery is ligated proximal to the gracilis artery branch, whereas in the mild surgery it is ligated distal to this branch. The gracilis artery feeds the major collateral vessels connecting the femoral and saphenous arteries; thus the area of the distal limb with detected flow (perfused sites) was expected and observed to be significantly less 24 h after severe vs. mild surgery in both genotypes (12). That a genotype-specific difference in perfusion was not observed 24 h after mild surgery highlights the importance of these collaterals in restoring flow to the distal limb and, moreover, suggests that the collateral vessels are likely similar in number and response to flow-dependent dilatory signals across genotypes, despite their compromised ability (9) to propagate signals upstream in the Cx40 Ϫ/Ϫ mice.…”

Advancing age and ischemia elevate the electric threshold to elicit spreading depolarization in the cerebral cortex of young adult rats

“…Taken the young adult age screened here, declining CBF compensation is suspected to root in altered vasoreactivity, rather than an age-related rarefaction of collateral vascular networks. 32 Possibly, altered characteristics of K ATP channel opening, ineffective adenosine signaling or restricted NO availability could potentially account for the less efficient flow compensation shortly after ischemia onset in our oldest age group.…”

The impact of aging on spreading depolarization in the intact and ischemic rat brain

“…Our data indicate that in the ischemia model used, perfusion stabilized and persisted at around 40% till the end of the ischemic period in young rats, but dropped below 20% in old rats, which falls below the CBF threshold of electrical failure of the nervous tissue 3 . Although age related cerebrovascular rarefaction may be held responsible for the poor flow compensation in aged rats 39 , we believe that the ischemia-induced perfusion deficit in our study was aggravated by the high incidence of inverse neurovascular coupling with SD in old animals. Thus, SDs associated with spreading ischemia likely impair the recovery of CBF, thereby worsening ischemia outcome.…”

“…The brain heavily relies on a constant blood supply for its undisturbed function. During the physiological aging process, unfavorable changes occur in the brain's microcirculation, including increased vascular wall stiffness 38 decreased vascular density 39 , impaired microvascular reactivity 40 , and weakened remodeling potential 39 . The additive outcome is lower basal cerebral blood flow, but more importantly, reduced, suboptimal local cerebral blood flow elevation in response to neural activity.…”

“…Our main observations of the SD-related CBF response are as follows: (1) the SD-coupled CBF response types, in which the hypoemic component is augmented at the expense of the hyperemic component, occur more frequently in the aged brain, (2) the combination of ischemia and old age predisposes the cortex for the evolution of spreading ischemia (inverse neurovascular coupling), and (3) the ischemia-related perfusion deficit progressively deepens in the old brain as opposed to the young. During physiological aging, unfavorable changes occur in the brain's microcirculation, including increased vascular wall stiffness 38 , decreased vascular density 39 , impaired microvascular reactivity 40 , and weakened remodeling potential 39 . The additive outcome is lower basal CBF, but more importantly, reduced, suboptimal local CBF elevation in response to neural activity, which is suggested to contribute to the shift to less obvious hyperemic and more prominent hypoemic elements in the SD-associated CBF response.…”